Circulating tumor DNA predicts response in Chinese patients with relapsed or refractory classical hodgkin lymphoma treated with sintilimab.

Abstract

BACKGROUND:

Blood-based biomarker such as circulating tumor DNA (ctDNA) has emerged as a promising tool for assessment of response to immunotherapy in solid tumors; But in hematological malignances, evidences are still lacking to support its clinical utility. In current study the feasibility of ctDNA for prediction and monitoring of response to anti-PD-1 therapy in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL) was assessed.

METHODS:

A total of 192 plasma samples from 75 patients with r/r cHL were collected at baseline and upon therapeutic evaluation. ctDNA were sequenced by targeting panels capturing frequently mutated genes in cHL and other hematological malignancies and then quantified. Analysis on: 1) Gene mutation profile and association of the gene mutations with progression-free survival; 2) Association of pre- and post-treatment ctDNA variant allelic frequencies with clinical outcome; (3) Correlation of the mutated genes with treatment resistance; were performed.

FINDINGS:

Somatic mutations were detected in 50 out of 61 patients by ctDNA genotyping. The mutations of CHD8 was significantly higher in patients with PFS ≥ 12 months. Baseline ctDNA was significantly higher in responders and a decrease of ctDNA ≥ 40% from baseline indicated superior clinical outcome. Strong agreement between ctDNA dynamic and radiographic response change during therapy was observed in majority of the patients. Furthermore, the mutations of B2M, TNFRSF14 and KDM2B were found to be associated with acquired resistance.

INTERPRETATION:

ctDNA could be an informative biomarker for anti-PD-1 immunotherapy in r/r cHL.

FUNDING:

This work was supported by Innovent Biologics, Eli Lilly and Companyhttps://doi.org/10.13039/501100002852, China National New Drug Innovation Program (2014ZX09201041-001 and 2017ZX09304015), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001) and National Key Scientific Program Precision Medicine Research Fund of China (2017YFC0909801). The funders had no role in study design, data collection, data analysis, interpretation or writing.

• Authors: Yuankai Shi, Hang Su, Yongping Song, Wenqi Jiang, Xiuhua Sun, Wenbin Qian, Wei Zhang, Yuhuan Gao, Zhengming Jin, Jianfeng Zhou, Chuan Jin, Liqun Zou, Lugui Qiu, Wei Li, Jianmin Yang, Ming Hou, Yan Xiong, Hui Zhou, Xinhua Du, Xiong Wang, Bo Peng
• Journal: EBioMedicine (EBioMedicine) Vol. 54 Pg. 102731 (Apr 2020) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 32304999 (Publication Type: Clinical Trial, Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• B2M protein, human
• Biomarkers, Tumor
• CHD8 protein, human
• Circulating Tumor DNA
• DNA-Binding Proteins
• F-Box Proteins
• Immune Checkpoint Inhibitors
• Receptors, Tumor Necrosis Factor, Member 14
• TNFRSF14 protein, human
• Transcription Factors
• beta 2-Microglobulin
• sintilimab
• Jumonji Domain-Containing Histone Demethylases
• KDM2A protein, human

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (genetics)
• Circulating Tumor DNA (genetics)
• DNA-Binding Proteins (genetics)
• Drug Resistance, Neoplasm
• F-Box Proteins (genetics)
• Female
• Hodgkin Disease (blood, drug therapy, genetics)
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Jumonji Domain-Containing Histone Demethylases (genetics)
• Male
• Middle Aged
• Mutation
• Receptors, Tumor Necrosis Factor, Member 14 (genetics)
• Transcription Factors (genetics)
• beta 2-Microglobulin (genetics)